The prefrontal cortex (PFC) is widely associated with cognitive and emotional functions,including attention, decision making, goal-directed behavior, and working memory. In a previous study, neural activity and morphological alterations in PFC were detected in patients with chronic pain. In addition, these patients had impaired performance on emotional decision-making tests and increased incidence of depressive and anxiety disorders. However, little is known about the time course of PFC blood flow during pain stimulation. Therefore, we examined the time course of PFC blood flow and the relationship between PFC activation and the subjective pain score during thermal stimuli.
　Fifteen healthy right-handed subjects participated in this study. Thermal stimuli were delivered to right dorsal forearm for 30 sec by a 5 × 5-mm peltier device (Unique Medical, Japan; UDH-300). Pain intensity was assessed using a visual analog scale (VAS) after the stimuli were delivered, and PFC blood flow data were obtained using near-infrared spectroscopy. The oxyhemoglobin (oxyHb) waveform was divided into four segments: the “baseline" segment for 10 s before the task period, the “first" segment for 10 s from the task period, the “middle"segment for 10 s from the end of the first segment, and the “last" segment of 10 s from the end of the middle segment. OxyHb data were averaged across the four segments and analyzed using Tukey's post hoc test. We calculated Spearman's correlation coefficient between the pain VAS score and oxyHb in each segment (first, middle, and last) during thermal stimuli.In addition, high-sensitivity (5 subjects) and low-sensitivity (5 subjects) groups were divided using the VAS score, and the differences in average oxyHb in each segment (first, middle, and last) between the high- and low-sensitivity groups were assessed using the Mann-Whitney U test.Statistically significant differences were expressed as p values less than 0.05.
　Furthermore, oxyHb of the last segment in the left dorsolateral PFC significantly decreased compared with those of the baseline and first segments. OxyHb of the first segment in the left side PFC decreased significantly in the high-sensitivity groups (mean VAS rating = 72.2 ± 5.6) compared with the low-sensitivity groups (mean VAS rating = 25.8 ± 8).
　Decrease in PFC blood flow during pain stimulation may induce atrophy and change in neural activation in PFCs of patients with chronic pain.

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　Sustained limb pain or back pain after surgery or injury occasionally shifts to chronic pain. In some cases, scar formed in damaged tissues can evoke chronic pain. However, there is a general lack of animal models to study chronic scar-related pain state.
　To develop a rat model with painful scar, a stick (3 mm of diameter) was inserted into the planta of unilateral hind-paw in anesthetized rats, followed by exfoliation of cutaneous and tendon tissues. Withdrawal responses were measured using von Frey filaments at different areas in the scar for four weeks. The test results for withdrawal responses suggested that a painful scar in a rat's planta resulted in reliable and quantifiable mechanical hyperalgesia lasting for four weeks. In the immunohistochemical study, increased expression of calcitonin gene-related peptide (CGRP) was observed in dorsal root ganglion (DRG) and in the spinal dorsal horn, and these changes are partly related to pathological pain state on the scar side.
　This model should contribute towards understanding the sensitization mechanism of painful scar and to develop new treatments for painful scar in humans.

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　Transient receptor potential (TRP) channels, nonselective cation channels, are gated by a variety of chemical and physical stimuli. Among them, there are TRPV1 and TRPA1 channels, both of which are thought to be involved in thermosensation and nociception. TRPV1 channels are activated by noxious hot temperature, protons and capsaicin while TRPA1 channels are by noxious cold temperature, mustard oil, cinnamon oil, ginger and garlic. These TRP channels are expressed in dorsal root ganglion (DRG) neurons; their activation in the central terminals of the neurons results in an increase in the spontaneous release of _L-glutamate to spinal dorsal horn, particularly substantia gelatinosa (SG; lamina II of Rexed), neurons from nerve terminals. Although local anesthetics (LAs) were recently reported to activate TRP channels which are cloned and expressed in DRG neurons, this has not been thoroughly examined yet in the CNS. We examined the effects of amine-type LAs (lidocaine, ropivacaine, prilocaine and levobupivacaine) and ester-type LAs (procaine, tetracaine and pramoxine) on glutamatergic spontaneous excitatory synaptic transmission in SG neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Bath-applied lidocaine dose-dependently and reversibly increased the frequency but not the amplitude of spontaneous excitatory postsynaptic current (sEPSC) recorded at a holding potential of -70 mV in SG neurons. The effect of lidocaine was unaffected by the voltage-gated Na⁺-channel blocker, tetrodotoxin (TTX), and the TRPV1 channel antagonist, capsazepine (Capz), but was inhibited by the non-selective TRP channel antagonist, ruthenium red (RR). In the same neuron, the TRPA1 channel agonist, allyl isothiocyanate, and lidocaine both increased sEPSC frequency. Tetracaine also increased sEPSC frequency in SG neurons in a manner insensitive to TTX and Capz while sensitive to RR, an action similar to that of lidocaine, but this action was delayed in onset by about 2.5 min compared to that of lidocaine. Like lidocaine and tetracaine, pramoxine increased sEPSC frequency; prilocaine had a tendency to do so. On the contrary, procaine, ropivacaine and levobupivacaine reduced sEPSC frequency. It is concluded that some of the amine-type and ester-type LAs activate TRPA1 channels in the SG to increase the spontaneous release of _L-glutamate from nerve terminals. This action could contribute to an increase in the excitability of SG neurons.

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　Galanin (Gal), a neuropeptide composed of 29 / 30 amino acid residues, is thought to play a pivotal role in various physiological functions including nociception. There is much evidence showing that Gal plays a role in modulating nociceptive transmission at the rat spinal cord level. Gal and three types (GalR1-3) of receptor for this are expressed in rat dorsal root ganglion neurons and spinal dorsal horn neurons. Behavioral studies have demonstrated that intrathecal administration of Gal modulates nociceptive transmission in rats. Cellular mechanisms for this Gal action, however, have not been fully examined yet. We have previously reported that Gal facilitates the spontaneous release of _L-glutamate from nerve terminals by activating GalR2/R3 without a change in _L-glutamate-receptor sensitivity and also produces a membrane hyperpolarization through GalR1 activation and/or depolarization in rat substantia gelatinosa (SG) neurons which play a crucial role in regulating nociceptive transmission through primary-afferent Aδ and C fibers from the periphery. In order to further know a role of Gal in regulating nociceptive transmission, in neurons where the postsynaptic response of Gal was not seen, we examined the action of Gal (0.1 µM) on dorsal root-evoked monosynaptic Aδ-fiber and C-fiber glutamatergic excitatory synaptic transmission, where the blind whole-cell patch-clamp technique was applied to SG neurons of an adult rat spinal cord slice attached with a dorsal root. Since SG neurons receive not only excitatory but also inhibitory inputs, the effect of Gal (0.1 µM) on inhibitory synaptic transmission was also examined. Gal reduced more effectively the peak amplitude of monosynaptic Aδ fiber than C-fiber excitatory postsynaptic current (EPSC) recorded at a holding potential of -70 mV; this was so in a neuron where both Aδ-fiber and C-fiber EPSCs were evoked. These Gal effects were mimicked by a selective GalR2/R3 agonist galanin (2-11) but not a GalR1 agonist M617. On the other hand, spontaneous and focally-evoked (GABAergic and glycinergic) inhibitory synaptic transmission was not affected by Gal (0.1 µM). These results indicate that Gal reduces the evoked release of _L-glutamate onto SG neurons from primary-afferent Aδ-fiber and C-fiber central terminals, possibly by activating GalR2/R3. This Gal effect could contribute to its regulation of nociceptive transmission.

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Gabapentin, an antiepileptic drug, selectively interacts with alpha-2 / delta 1 calcium channel subunits (CACNA2D1), and has an analgesic effect on neuropathic pain. Neuropathic pain is known to be accompanied by the up-regulation of the expression of many genes. We observed the involvement of the analgesic effect of gabapentin and the alteration of the expression of genes in an inferior alveolar nerve-transected rat neuropathic pain model, in which IAN transection induced allodynia in whisker pads innervated by uninjured neurons.
We determined the up-regulation of the expression of several genes in the trigeminal ganglia of IAN-transected rats, including those for neuropeptides, GDNF receptor and CACNA2D1;however, these up-regulations were confined almost exclusively to injured neurons, and were not detected in the neurons innervating the allodynia area. Upon suppression of tactile allodynia in IAN-transected rats by intrathecal administration of gabapentin, the increased gene expression levels did not change, other than that of CACNA2D1, whose expression was reduced with the attenuation of allodynia.
These findings indicate that gabapentin relieves the allodynia developed in the cutaneous region innervated by uninjured neurons, but that the main target of gabapentin is the CACNA2D1 expressed in injured neurons.

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　Neurotropin^® (NTP), a non protein extract from inflamed rabbit skin inoculated with vaccinia virus, is well known as an analgesic for chronic pain such as low back pain and postherpetic pain. In previous study, we revealed that NTP activated monoaminergic descending pain inhibitory system in SART (specific alternation of rhythm in temperature) stressed animals. To clarify the details of antinociceptive mechanisms of NTP, we investigated the influence of chemical denervation of monoaminergic neurons on the antinociceptive effect of NTP in SART-stressed rats. First, serotonergic neurons of nucleus raphe magnus (NRM) were chemically denervated by injection of 5,7-dihydroxytryptamine (50 nmol / 1 µL / site). Chemical denervation of NRM serotonergic neurons decreased the contents of spinal serotonin but not noradrenaline and dopamine, and decreased nociceptive threshold in rats. SART stress decreased nociceptive threshold in non-denervated rats but not in denervated rats whose threshold was already decreased. NTP (200 NU/kg, p.o.) showed an antinociceptive effect in non-denervated rats exposed to SART stress but had no effect in NRM-denervated rats exposed to SART stress. Next, we denervated spinal noradrenergic terminals by intrathecal injection of 6-hydroxydopamine (1 µmol / 10 µL / site) because some noradrenergic neurons are descending from some supraspinal noradrenergic nucleus to spinal cord. Chemical denervation of spinal noradrenergic neurons decreased the contents of spinal nor adrenaline but not serotonin and dopamine in rats. Similar to denervation of NRM serotonergic neurons, nociceptive threshold was decreased by chemical denervation of spinal noradrenergic neurons. SART stress decreased the nociceptive threshold in non-denervated rats, and that was improved by NTP (200 NU/kg, p.o.). SART stress did not affect the decreased threshold in denervated rats and NTP (200 NU/kg, p.o.) had no effect in denervated rats exposed to SART stress. These results suggest that antinociceptive effects of NTP in SART-stressed rats involve the activation of monoaminergic descending inhibitory neurons.

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